Central nervous system (CNS) diseases and disorders represent the largest and fastest growing area of unmet medical need. Over 1.5 billion people worldwide, including over 100 million people in the US, suffer from CNS diseases or disorders. This project is aimed at finding a new way to get therapeutic drugs to CNS more effectively, more safely, and more conveniently. It is hypothesized that dendrimer nanoparticles carrying brain- specific ligand and a high payload of CNS drugs will cross the BBB in significant amounts via transcytosis. It is further hypothesized that brain-targeted dendrimer nanoparticles can cross the buccal membrane to get into the systemic circulation. To test the above hypotheses, the following three specific aims are proposed: Aim 1: Synthesize and characterize a novel brain-targeted dendrimer-based nanoparticulate drug delivery system;Aim 2: Assess the brain-targeting ability and permeability of brain-targeted dendrimer nanoparticles across the BBB in vitro;Aim 3: Formulate a mucoadhesive PEG/gelatin IPN hydrogel for buccal administration of brain-targeted dendrimer nanoparticles, and determine the controlled release kinetics and permeability across the buccal membrane. To address Aim 1, a layer-by-layer synthesis will be carried out to create a brain- targeted dendrimer drug delivery system. The biocompatibility, toxicity, and immunocompatibility of dendrimers will be modulated through proper chemical modification at the periphery, and their composition, shape, and size will be tuned to optimize therapeutic efficacy and delivery efficiency. To address Aim 2, a dynamic in vitro (DIV)-BBB model will be employed to test the synthesized brain-targeted dendrimer nanoparticles in terms of targeting ability, permeability efficiency across the BBB, and transcytosis. To address Aim 3, a dosage form based on PEG/gelatin IPN hydrogel will be formulated to deliver brain-targeted dendrimer nanoparticles. Drug release kinetics and permeability across the buccal membrane will be evaluated. To demonstrate the potential clinical relevance, a well-characterized opioid peptide, DPDPE (NH2-Tyr1-D- Pen2-Gly3-Phe4-D-Pen5-OH) will be used as a model drug. Its definitive CNS-mediated analgesia, well- defined opioid receptors, and in vitro and in vivo data readily available in the literature will allow us to compare and confirm the efficacy of the established brain-targeted dendrimer drug delivery system e with a relatively high level of confidence. The unique integration of developing a new brain-targeted drug delivery system based on dendrimers and exploring buccal administration for its delivery will result in an innovative non-invasive treatment to deliver drugs to the brain across the BBB selectively and collectively, thus improving therapeutic effectiveness and reducing side effects. The ease of buccal drug administration will reduce treatment cost and societal burden, increase patient compliance as well as improve the quality of the overall treatment. PUBLIC HEALTH RELEVANCE: This project will develop a novel brain-targeted nanomedicine based on dendrimers to deliver drugs to the brain across the blood-brain barrier (BBB) selectively and collectively, thus improving therapeutic effectiveness and reducing side effects. This project will also explore buccal administration for systemic delivery of the proposed nanomedicine to reduce treatment cost and societal burden, increase patient compliance as well as improve the quality of the overall treatment.